Emerging concepts and therapeutic implications of β-adrenergic receptor subtype signaling

The stimulation of beta-adrenergic receptor (beta AR) plays a pivotal role in regulating myocardial function and morphology in the normal and failing heart. Three genetically and pharmacologically distinct beta AR subtypes, beta(1)AR, beta(2)AR, and beta(3)AR, are identified in various types of cells. While both beta(1)AR and beta(2)AR, the predominant beta AR subtypes expressed in the heart of many mammalian species including human, are Coupled to the G(s)-adenylyl cyclase-cAMP-PKA pathway, beta(2)AR dually activates pertussis toxin-sensitive G(i) proteins. During acute stimulation, beta(2)AR-G(i) coupling partially inhibits the G(s)-mediated positive contractile and relaxant effects via a G(i)-G(beta gamma)-phosphoinositide 3-kinase (PI3K)-dependent mechanism in adult rodent cardiomyocytes. More importantly, persistent beta(1)AR stimulation evokes a multitude of cardiac toxic effects, including myocyte apoptosis and hypertrophy, via a calmodulin-dependent protein kinase II (CaMKII)-, rather than cAMP-PKA-, dependent mechanism in rodent heart in vivo and cultured cardiomyocytes. In contrast, persistent beta(2)AR activation protects myocardium by a cell Survival pathway involving G(i), PI3K, and Akt. In this review, we attempt to highlight the distinct functionalities and signaling mechanisms of these beta AR subtypes and discuss how these subtype-specific properties of beta ARs might affect tile pathogenesis of congestive heart failure (CHF) and tile therapeutic effectiveness of certain beta-blockers in tile treatment of congestive heart failure. (c) 2005 Published by Elsevier Inc.